Abstract
Early life radiation exposure causes abnormal brain development, leading to adult depression. However, few studies have been conducted to explore pre- or post-natal irradiation-induced depression-related neuropathological changes. Relevant molecular mechanisms are also poorly understood. We induced adult depression by irradiation of mice at postnatal day 3 (P3) to reveal hippocampal neuropathological changes and investigate their molecular mechanism, focusing on MicroRNA (miR) and its target mRNA and protein. P3 mice were irradiated by γ-rays with 5Gy, and euthanized at 1, 7 and 120 days after irradiation. A behavioral test was conducted before the animals were euthanized at 120 days after irradiation. The animal brains were used for different studies including immunohistochemistry, CAP-miRSeq, Real-Time Quantitative Reverse Transcription PCR (qRT-PCR) and western blotting. The interaction of miR-34a-5p and its target T-cell intracytoplasmic antigen-1 (Tia1) was confirmed by luciferase reporter assay. Overexpression of Tia1 in a neural stem cell (NSC) model was used to further validate findings from the mouse model. Irradiation with 5 Gy at P3 induced depression in adult mice. Animal hippocampal pathological changes included hypoplasia of the infrapyramidal blade of the stratum granulosum, aberrant and impaired cell division, and neurogenesis in the dentate gyrus. At the molecular level, upregulation of miR-34a-5p and downregulation of Tia1 mRNA were observed in both animal and neural stem cell models. The luciferase reporter assay and gene transfection studies further confirmed a direct interaction between miR-34a-5p and Tia1. Our results indicate that the early life γ-radiation-activated miR-34a-5p/Tia1 pathway is involved in the pathogenesis of adult depression. This novel finding may provide a new therapeutic target by inhibiting the miR-34a-5p/Tia1 pathway to prevent radiation-induced pathogenesis of depression.
Highlights
Depression is one of the most significant and long-term consequence of radiation exposure among the survivors of nuclear accidents or wars [1,2,3,4] and is associated with brain-structural changes including reduced dentate gyrus size and altered hippocampal volume [5,6,7,8,9,10,11,12]
While it has been well documented that oxidative stress and neuroinflammation are involved in radiation-induced brain damage, whether brain microRNA and its target gene are involved in radiation-induced hippocampal structural changes and subsequent depression remains unknown
This study aimed to examine if the acute irradiation with 5Gy at postnatal day 3 (P3) induced adult depression
Summary
Depression is one of the most significant and long-term consequence of radiation exposure among the survivors of nuclear accidents or wars [1,2,3,4] and is associated with brain-structural changes including reduced dentate gyrus size and altered hippocampal volume [5,6,7,8,9,10,11,12]. The therapeutic effect achieved by promoting neurogenesis to improve depression symptoms further supports the “neurogenesis hypothesis of depression” [11,15,16]. These neuropathological changes may be induced by pre- or post-natal radiation exposure [17,18,19,20,21,22,23]. Establishment of the relationship between brain miR-34a-5p, its target gene and the impairment of neurogenesis or small dentate gyrus may provide new clues for understanding the mechanism of the development of depression and for novel therapeutic approaches to prevent the genesis of depression
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